Our current work in the NIAAA consortium on the Neurobiology of Adolescent Drinking in Adulthood (NADIA) has yielded four key findings of critical importance regarding the consequences of adolescent intermittent ethanol (AIE). These consequences: a) differ dramatically with exposures during early-mid versus late adolescence; b) are sex-specific; and include c) induction of social anxiety, and d) the persistence of adolescent-typical phenotypes, including adolescent-typical responses to ethanol into adulthood. Our current proposal will address critical gaps arising from this work. Aim 1 will assess whether early-mid adolescent AIE exposure (analogous to early initiation of use in adolescence) alters social/affective/reward domains influenced by subcortical limbic systems whose activity is particularly prevalent at that time, whereas AIE in late adolescence (analogous to the late adolescent/emerging adulthood period in humans where binge drinking is particularly pronounced) produces alterations in tasks requiring integrity of late maturing prefrontal areas. Effects are predicted to be sex-specific, with early AIE effects more pronounced in males and late AIE consequences in females. Aim 2 will focus on neural substrates underlying the marked social anxiety-like behavior induced by early AIE in males, with a focus on two peptides critically involved in social behavior: oxytocin (OXT) and vasopressin (AVP). Psychopharmacological approaches along with assessment of levels of OXT, AVP and their receptors, as well as associated epigenetic modifications in two key regions involved in social anxiety (amygdala and hypothalamus), will be used to test the hypothesis that social anxiety in males is associated with a shift in balance of OXT and AVP toward AVP. Lastly, Aim 3 will assess whether the persistence of well-characterized adolescent-typical ethanol sensitivities into adulthood following AIE relates to perturbations in excitatory-inhibitory balance. Both psychopharmacological and molecular approaches will be used to test this hypothesis, with a particular emphasis on glutamate NR2B and AMPA and extrasynaptic GABAA receptors along with vesicular transporter ratios. Studies in both Aims 2 and 3 will be conducted with an eye toward identification of pharmacotherapeutic approaches to reverse AIE effects.